Chimeric Antigen Receptor (CAR)-Engineered T Cells for Cancer Therapy
Using gene-transfer techniques, it is now possible to genetically modify T-cells to stably express antibodies on their surface, thus conferring new antigen specificity. Chimeric antigen receptor T-cells (CAR T-cells) are engineered to combine an antigen recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein. Even though chimeric antigen receptors are able to initiate activation of T-cells in a similar way that endogenous T-cells do, there has been only limited success attempting to expand the population of these CAR T-cells in vivo 1. The original concept of the chimeric antigen receptor (CAR; also known as T-bodies or chimeric immune receptors) was described over 15 years ago by Zelig Eshhar and colleagues working at the Weissman Institute in Israel. This theoretical approach was based upon the idea that receptors on the surface of a T-cell would enable the T-cell to identify intact protein antigens present on the surface of a target cell. T-cells typically function by recognizing peptide antigens that are presented to them by together with major histocompatibility complex (MHC) proteins by the target cell. However, one aspect of tumor biology that makes tumors so hard to treat is that they actually down-regulate the expression of MHC on the surface of the tumor cells, thereby effectively rendering themselves invisible to the body's T-cell defense system. Binding of the T-cell receptor to the MHC complex is a required for T- cell effector function. However, the original CAR T-cell hypothesis was based on the idea that direct recognition of protein antigens through a CAR would effectively render tumor cells visible to they body's T-cell immuno-surveillance system once more 2, 3, 4. Reprogramming the Immune System to Fight Cancer The short video at the top of this Wikia page briefly describes how scientists are now able to effectively reprogram a person's immune system to attack and destroy their own cancer cells. This may sound like science fiction, but with the advanced gene-transfer molecular biology tools available today it is a very promising reality. Gene Therapy Procedure Depicted in the video at the top of the page is one example of how CAR T-cell technology is currently being used to treat cancer. T-cells from a patient with chronic lymphocytic leukemia (CLL) can be removed via leukapheresis, treated with a lentiviral vector expressing a chimeric antigen receptor that is specific for the B-cell antigen CD19 coupled to the signaling domains of CD137 (a costimulatory T-cell receptor) and CD3-zeta (a T-cell antigen receptor signal transduction component), and subsequently reinfused into the patient. This procedure genetically modifies the patients T-cells so that they stably express the new antibodies on their surface, thus providing the patient with new antigen specificity so that the genetically modified CAR T-cells attack and destroy the leukemia cells 4. Implications It has been speculated that the chemotherapy may actually enhance the effects of chimeric antigen receptor T cells (CAR T-cells) by increasing engraftment and migration of CAR T-cells to tumor cells, and also by potentially enhancing the ability of CAR T-cells to kill stressed tumor cells that would otherwise survive chemotherapy treatments. Unlike antibody-mediated therapies, chimeric antigen receptor–modified T-cells have the potential to replicate in vivo, and thus long-term persistence of these cells can lead to sustained tumor control and even to complete remission of the cancer 3, 4. References 1. Ramos CA & Dotti G (2011) Chimeric Antigen Receptor (CAR)-Engineered Lymphocytes for Cancer Therapy. Expert Opin Biol There. 11(7):855–873 2. Riches JC, Ramsay AG, & Gribben JG (2012) Immune Reconstitution in Chronic Lymphocytic Leukemia. Current Hematologic Malignancy Reports. 7(1):13-20. 3. Curran KJ, et al. (2012) Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. J Gene Med. 14:405–415. 4. Lipowska-Bhalla G, et al. (2012). Targeted immunotherapy of cancer with CAR T cells: achievements and challenges.'' Cancer Immunol. Immunother.'' 61:953–962.